Basic esters of 9, 10-dihalogenated 9, 10-dihydro-9, 10-ethanoanthracene-11-carboxylic acids and their derivatives



Patented Mar. 30, 1954 BASIC ESTERS F 9,10-DIHALOGENATED 9,10 DIE-HYDRO 9,10 ETHANOANTHRA- GENE-ll-CARBOXYLEC ACIDS AND THEIR DERIVATIVES William W. Jenkins, Morton Grove, Ill, assignor to G. D. Searle & C0,, Shicago, 1111., a corporation of Illinois No Drawing. Application June 3, 1952, Serial No. 291,575

The present invention relates to a new i group of basic esters of polycarbocyclic acids, and, par" ticularly, to the basic ester of 9,1O-dihalogenated 9,10 dihydro-9,l0-ethanoanthracene-llcarboxylic acids and their derivatives. These esters and their non-toxic salts which constitute the invention are represented by the following general structural formula wherein X is a halogen atom, Y and Z are mernbers of the class consisting of hydrogen and lower alkyl radicals, A is a saturated lower bivalent hydrocarbon radical containing at least 2 carbon atoms and NRR' is either a lower dialkylamino radical or a nitrogen-containing heterocyclic radical attached through a nitrogen in the heterocycle to the radical A.

AS shown in the foregoing structural formula the ethane-bridge may be unsubstituted or loweralkylated by the groups referred to as Y and Z which, besides hydrogen, can represent such lower alkyl radicals as methyl, ethyl, propyl, butyl, amyl, and hexyl.

The radical A is derived from such straightchained or branch-chained aliphatic hydrocarbon radical as ethylene, propylene, butylene, amylene, hexylene or a polymethylene radical such as trimethylene, tetramethylene, pentawherein B is either an ethyleneoxyethylene radical, as in the case of mcrpholine Or an allzylene chain containing 4 to '7 carbon atoms, i to 5 of which are in nuclear position as in the case of and 2,6-1upetidino radicals.

12 Claims. (01. 260-469) The organic bases described herein form nontoxic salts with a variety of inorganic and strong organic acids including sulfuric, phosphoric, hydrochloric, hydrobrornic, hydriodic, sulfamic, citric, lactic, maleic, malic, succinic, tartaric, cinnamic, acetic, benzoic, gluconic, oxalic, ascorbic and related acids. They also form quaternary ammonium salts with a variety of organic esters of sulfuric, hydrohalic and aromatic sulfonic acids. Among such esters are methyl chloride, bromide and iodide; ethyl chloride, propyl chloride, butyl bromide, isobutyl chloride, benzyl chloride, phenethyl chloride, naphthylmethyl chloride, dimethyl sulfate, methyl benzenesulionate, ethyl toluenesulionate, ethylene chlorohydrin, propylene chlorohydrin, allyl chloride, methallyl bromide and crotyl bromide.

The acid which constitute the starting materials for this invention are prepared by a Diels- Alder addition of a compound of the type wherein X is hydrogen or a lower alkyl group, and Y and Z are defined as hereinabove to a 9,10-dihalogenated anthracene. Esterification is carried out preferably by refluxing a solution of the acid with an equivalent of the aminoalkyl halide in an inert solvent such as Z-propanol or acetone. The hydrohalide of the basic ester is thus produced and is separated as such or neutralised and extracted as the basic ester. The basic ester can also be prepared by reacting the acid halide with an excess of the amino alcohol, neutralizing the reaction mixture, and extracting the basic ester.

The compound which constitute the present invention are useful as intermediates in chemical synthesis. They are also useful as medicinal agents. They are potent. blood pressure lowering drugs. The simple addition salts are diuretics. The quaternary salts are ganglion blocking agents.

My invention is disclosed in further detail by the following examples which are set forth for the purpose of illustrating this invention, but are in. no way to be construed as limiting it is spirit or in scope. It will be apparent to those skilled in the art of organic synthesis that many con- .pyrrolidino, piperidino, Zfi-dimethylpyrrolidino ventional modifications in methods; conditions, and materials can be adapted without departing therefrom. In these examples temperatures are given uncorrected in degrees centigrade' 0.), pressure during vacuumdistillation in millimeters (innmfof mercury, and quantities of materials in parts by weight.

3 EXAMPLE 1 9,10 dihydro 9,10-dibromo-9,10-ethanoanthmcene-11 -carbomylic acid ester of fl-diethylaminoethanol A mixture of 404 parts of 9,10-dibromoanthracene and 400 parts of methyl acrylate is heated in a bomb at 190-200 C. for 6 hours. The contents are then heated at reflux temperature with 1600 parts of methanol and 160 parts of potassium hydroxide in 160 parts of water for 4 hours. The mixture is concentrated in vacuo and the residue is suspended in 6000 parts of water, washed with ether, clarified with decolorizing charcoal and acidified with dilute hydrochloric acid. The precipitated 9,10-dihydro-9,10-dibromo-9,IO-ethanoanthracene-ll-carboxylic acid is collected on a filter and recrystallized from methanol. It melts at about 248-250" C.

A mixture of 408 parts of this acid and 150 parts of fi-chloroethyldiethylamine in 1200 parts of anhydrous 2-propanol is heated at reflux tern-- perature for 7 hours. Upon standing at room temperature a precipitate is formed which is collected on a filter and then dissolved in water. The aqueous solution is washed with ether and then rendered alkaline by addition of sodium hydroxide and extracted with ether. The ether extract is dried over anhydrous calcium sulfate, filtered and evaporated. The product decomposes upon distillation.

105 parts of the crude fi-diethylaminoethanol ester of 9,10-dihydro-9,10-dibromo-9,10-ethanoanthracene-l1-carboxylic acid are dissolved in absolute ether, clarified with charcoal, and diluted with 2000 parts of ether. The ether solution is treated with one equivalent of a solution of hydrogen chloride in anhydrous 2-propanol. Upon chilling the hydrochloride of the di ethylaminoethanol ester of 9,10-dihydro-9,10-dibromo-9,10-ethanoanthracene-1l-carboxylic acid precipitates, which melts at about 200-200.5 C. with decomposition. Recrystallization from 2- propanol does not raise the melting point.

EXAIWPLE 2 9,10-dihydro-9,10-dibromo 9,10 ethanoanthracene-11 -carboxylic acid ester of e-hydrorzzethyldiethylmethylammonium bromide A solution of 105 parts of the fi-diethylarninoethyl 9,10 dihydro 9,10-dibromo-9,10-ethanoanthracene-ll-carboxylate in 240 parts of butanone is treated with parts of methyl bromide in a shielded pressure reactor at room temperature for one hour, during which time a heavy oil separates. The reaction is completed by heating for one hour at C., and on standing, the oil crystallizes. The crystals are collected on a filter and recrystallized from a mixture of 2-propanol and ethyl acetate. The 9,10-dihydro- 9,10-dibromo-9,10-ethanoanthracene-ll-carboxylic acid ester of 13-hydroxyethyldiethylmethylammonium bromide, which melts at about 185- 186 C. with decomposition, has the structural formula 4 EXAMPLE 3 9,10 dihydro 9,10 dibromo 12 methyl-9,10-

ethanoanthracene-Il-carboacylic acid ester of B-diethylaminoethanol A mixture of 303 parts of dibromoanthracene and parts of crotonic acid is heated in a bomb at C. for 8 hours. After cooling the reaction mixture is extracted with 5000 parts of 5% sodium hydroxide and filtered. The filtrate is chilled and the solid sodium salt collected on a filter, suspended in water and acidified by ailclition of dilute hydrochloric acid. The precipitate oi the free acid is collected on a filter and recrystallized from xylene. It melts at about 27l-27l.5 C.

A mixture of 365 parts of 9,10dihydro-9,l0- dibromo-l2-methyl-9,10-ethanoanthracene i1 carboxylic acid and 120 parts of B-chloroethyldietl'iylamine in 1200 parts of anhydrous 2-propanol is heated at reflux temperature for 6 hours. Within an hour the mixture sets to a semi-solid mass. The reaction product is collected on a filter and suspended in water. After alkalinization the aqueous suspension is extracted with ether and the ether extract is dried over anhydrous potassium carbonate, filtered and evaporated. The crude oily fi-diethylaminoethanol ester or 9,10-dihydro-9,10-dibromo-l2-methyl- 9,10-ethanoanthracene-ll-carboxylic acid is dissolved in ether and treated with one equivalent of a 25% solution of hydrogen chloride in anhydrous 2-propanol. There is an immediate precipitation of White crystals. The hydrochloride is recrystallized from ethanol with charcoal clarifications. It melts at about 233-234" C. with decomposition.

EXAMPLE 4-.

9,10 diizydro 9,10 dibromo 12 methyl-9,10-

ethrmoanthracene-ll-carboa:ylic acid ester of p hydroazyethyldiethyZmethylammonium bromade A mixture of parts of the B-diethylaminoethanol ester of 9,10-dihydro-9,l0-dibromo-l2- methyl 9,10 ethanoanthracene ll-carboxylic acid and 61 parts of methyl bromide in 240 parts of butanone is heated for one hour in a shielded pressure reactor and then chilled. The resulting crystals are collected on a filter and recrystallized from a mixture of 2-propanol and ethyl acetate. The 9,10 dihydro 9,10-dibromo-l2- methyl 9,10 ethanoanthracene ll-carboxylic acid ester of B-hydroxyethyldiethylmethylammonium bromide, which melts at about ZOO-203 C. With decomposition, has the structural formula EXAMPLE 5 9,10-dihydr0-9,10 dichloro IZ-ethyZ-QJO-ethanoanthracene-I1-carborylic acid ester of 'y (N-morpholz'nc) propanol A mixture of 610 parts of Z-pentenoic acid and 100 parts of 9,10-dichloroanthracene is heated in a bomb at about 170 C. for 6 hours. cooled and 1 position.

extracted with a dilute aqueous solution of sodium hydroxide. The extract is washed with ether, rendered acid by addition of dilute hydrochloric acid, filtered and extracted with ether. The ether extract is stirred with charcoal, filtered and evaporated to yield the 9,10-dihydro-9,10-dichloro-12- ethyl-9, IO-ethanoanthracenel l -carboxylic acid.

A mixture of 347 parts of this acid and 165 parts of N-( -chloropropyl)morpholine in 20cc parts of absolute 2-propanol is heated at reflux temperature for 18 hours. The reaction mixture is partially concentrated and the residue suspended in water, washed with ether, andrendered alkaline by the addition of sodium hydroxide. The base is extracted with ether and the ether extract is washed with water, dried over anhydrous potassium carbonate, filtered, stirred with decolorizing charcoal and evaporated. The clear viscous oil is high boiling and decomposes on vacuum distillation. The 'y-(N-morpholino) propanol ester of 9,1'0dihydro-9,10-dichloro-12 ethyl- 9,10-ethanoanthracene 11 carboxylic acid has .the structural formula EXAMPLE 6 9,1 -dihydro-9,1 0 dibromo-I 1 -methyZ- 9,1 O-ethanoanthracene-IZ-carboxylic acid ester of B- diethylaminoethanol In a bomb 404 parts of 9,1(i-dibromoanthracene and 280 parts of methyl methacrylate are heated at 170 C. for 8 hours and the resulting mixture is refluxed for 12 hours with 1600 parts of math J anol and a solution of 406 parts of potassium hydroxide in 409 parts or" water. The solvent is evaporated in vacuo and the residue is extracted with water. This extract is washed with ether,

clarified with charcoal and acidified with dilute hydrochloric acid. The 9,1G-dihydro-QJO-dibromo-1l-methyl-9,l0 ethanoanthracene ll-carboxylic acid precipitates which, recrystallized from xylene, melts at about EST-239 with decomposition.

A mixture of 422 parts of this acid and 150 parts of s-chloroethyldiethylamine in 1208 parts of anhydrous 2-propano1 is heated at reflux temperature for 7 hours and permitted to stand. After trituration with 3800 parts of ether, the product is collected on a filter and suspended in water. After alkalinization the base is extracted with ether and the extract washed with water, dried over anhydrous potassium carbonate, filtered and evaporated.

420 parts of the B-diethylaminoethanol ester of 9,1il-dihydro-9,1G dibromo-11methyl-9,l0-ethanoanthracene-ll-carboxylic acid, obtained as a viscous oil, are dissolved in 6000 parts of anhydrous ether and treated with one equivalent of hydrogen chloride in absolute ethanol. The immediately precipitating white hydrochloride is collected on a filter and recrystallized from 2- propanol. It melts at about 205 C. with decom- 6 EXAMPLE 7 9,10-dihydro-9,10 dibromo-II-methyl-9,10-ethanoanthracene 11 carboazylz'c acid ester of c hydroasyethyldiethylmethylammonium, bromide sition, has the structural formula B cm o can B r C-OH3 02115 Treatment of a solution of 3 moles of the bromide in 2-propano1 with one mole of silver citrate and 2 moles of citric acid by stirring at room temperature, removal of the precipitated silver bromide by filtration and concentration of the filtrate yields the dihydrogen citrate.

EXAMPLE 8 9,10-dz'hyd'ro 9,10 dichloro-l1-ethyZ-9,Z0-ethanocnthrccene-Ii-carborylic acid ester of 'ydiisopropylaminopropanol In a bomb a mixtur of parts of 9,10-dichloroanthracene and 100 parts of z-ethylacrylic acid is heated at about C. for 7 hours. After cooling the reaction mixture is extracted with 5% aqueous sodium hydroxide solution. The extract is washed with ether, clarified with charcoal and acidified with dilute hydrochloric acid. The precipitated acid is collected on a filter.

A solution of 178 parts of -chloropropyldiisopropylamine in 2860 parts of anhydrous propanol is heated with 347 parts of the 9,10-dihydro- 9,10 dichloro-1l-ethyl-9,10-ethanoanthracenell-carboxylic acid at reflux temperature for 10 hours and then concentrated. The residue is extracted with water and the aqueous solution washed with ether, rendered alkaline and then extracted with ether. The ether extract is dried over anhydrous calcium sulfate, stirred with decolorizing charcoal, filtered and evaporated, yielding the -diisopropylaminopropanol ester of 9,l0-dihydro-9,l0-dichloro 11 ethyl-9,10- ethanonanthracene-ll-carboxylic acid as a clear viscous oil which tends to decompose on distillation. It has the structural formula 7 EXAMPLE .9

9,10-dihydro 9,10 dichZoro-l1,12-diethyZ-9J0- ethanoanthracene-II-carborylic acid ester of N ,s-hydrorcyethyl) -2,6-Zupetiline A mixture of 780 parts of 2-ethyl-2-pentenoic acid and 1900 parts of 9,1G-dichloroanthracene is heated in a comb for 8 hours at 175 (3., and cooled and extracted with a large volume of aqueous sodium hydroxide solution. This extract is washed with ether, clarified with charcoal, acidified with dilute hydrochloric acid and then extracted with ether. This extract is solvent stripped in vacuo, leaving as a residue the 9,10- dihydro 9,l0-dich1oro 11,l2-diethyl-9,l0-ethanoanthracenel. l -carhoxylic acid.

3'75 parts of this acid are heated with a solution of 175 parts of N(,8-chloroethyl)-2,6 lupetidine in 2200 parts of anhydrous Z-propanol at reflux temperature for hours and then extracted with water. The aqueous extract is Washed with ether, rendered alkaline and extracted with ether. The ether extract is dried over anhydrous potassium carbonate, washed with water, stirred with decolorizing charcoal, filtered and evaporated. The resulting N-(e-hydroxyethyl)-2,6-lupetidine ester of 9,10-dihydro 9,10-dichloro-l1,l2-diethyl-9,ll-ethanoanthracene-ll-carboxylic acid is obtained as a clear, amber, viscou oil which decomposes on distillation. It has the structural formula 1. The group of new esters consisting of the bases represented by th compounds of the structural formula Z halogen C /Y halogen C R C O O -AN and the non-toxic acid addition and quaternary salts thereof, wherein Y and Z are members of the class consisting of hydrogen and lower alkyl radicals, A is a lower alkylene radical containing at least 2 carbon atoms, and NRR' is a member of the class consisting of lower dialkylamino radicals, morpholino radicals and radicals wherein R and R are combined to form a lower alkylene radical containing t to '7 carbon atoms, 4 to 5 of which are in nuclear position, and wherein th halogen atoms are of an atomic weight greater than 20.

2. The esters oi! the structural formula halogen 3. The esters of the structural formula Br CHCOOAN(lower alkyl); a wherein A is a lower alkylene radical containing at least 2 carbon atoms.

4. The esters of the structural formula halogen CH2 (lower alkyl) halogen C\ wherein A is a lower alkylene radical containing at least 2 carbon atoms and wherein the halogen atoms are of an atomic weight greater than 20.

5. The esters of the structural formula Br CH2 COOAN(lowcr alky1)2 wherein A is a lower alkylene radical containing at least 2 carbon atoms.

6. 9,10 dihydro-9,l0-dibromo-1l-methyl-9,10- ethanc-anthracene-ll-carlaoxylic acid ester of 13- diethyiaminoethanol.

'7. The esters of the structural formula Cl CH2 /(lower alkyl) of C C OOA-N(lower alkyl);

wherein A is a lower alkylene radical containing at least 2 carbon atoms.

8. The esters of the structural formula halogen C H @fQ (lower alkyl) halogen C O O'AN (lower alkyl);

wherein A is a lower alkylene radical containing 9 10 at least 2 carbon atoms and wherein the halogen 11. The esters of the structural formula atoms are of an atomic weight greater than 20.

9. The esters of the structural formula Br on (lower alkyl) 5 1 000 A N( ower alkyl);

Halogen wherein A is a lower alkylene radical containing at least 2 carbon atoms and wherein the halogen atom is of an atomic weight greater than 20.

wherein A is a lower alkylene radical containing at least 2 carbon atoms.

The esters of the structural mrmula 16 12. The esters of the structural formula halogen CH: Br CH:

I halogen CH Br 3 CH;

COQA-N(10W6l alkyl); COOCHICHRN(C2H5)I 1 3 alogen wherein the halogen atom is of an atomic weight wherein A is a lower alkylene radical containing greater than 20.

at least 2 carbon atoms and wherein the halogen atoms are of an atomic weight greater than 20 WILLIAM JENKINS and. B is a non-toxic anion. No references cited. 

1. THE GROUP OF NEW ESTERS CONSISTING OF THE BASES REPRESENTED BY THE COMPOUNDS OF THE STRUCTURAL FORMULA 